A genome-wide CRISPR screen identifies GRA38 as a key regulator of lipid homeostasis during Toxoplasma gondii adaptation to lipid-rich conditions
Intracellular parasites like Toxoplasma gondii scavenge host nutrients, particularly lipids, to support their growth and survival. Although Toxoplasma is known to adjust its metabolism based on nutrient availability, the mechanisms that mediate lipid sensing and metabolic adaptation remain poorly understood. Here, we perform a genome-wide CRISPR screen under lipid-rich (10% Fetal Bovine Serum (FBS)) and lipid-limited (1% FBS) conditions to identify genes critical for lipid-responsive fitness. We identify the Toxoplasma protein GRA38 as a lipid-dependent regulator of parasite fitness. GRA38 exhibits phosphatidic acid (PA) phosphatase (PAP) activity in vitro, which is significantly reduced by mutation of its conserved DxDxT/V catalytic motif. Disruption of GRA38 leads to the accumulation of PA species and widespread alterations in lipid composition, consistent with impaired PAP activity. These lipid imbalances correlate with reduced parasite virulence in mice. Our findings identify GRA38 as a metabolic regulator important for maintaining lipid homeostasis and pathogenesis in Toxoplasma gondii.
Authors
- Parag Maru (ORCID: https://orcid.org/0000-0001-5607-2677)
- Cyrille Y. Botté (ORCID: https://orcid.org/0000-0002-2245-536X)
- Yifan Wang (ORCID: https://orcid.org/0000-0001-9451-0041)
- Samuel Duley (ORCID: https://orcid.org/0000-0002-3419-8057)
- Shruthi Krishnamurthy (ORCID: https://orcid.org/0000-0003-4540-6613)
- Tatiana C. Paredes-Santos (ORCID: https://orcid.org/0000-0002-5355-1012)
- Jeroen P. J. Saeij (ORCID: https://orcid.org/0000-0003-0289-7109)
- Mebratu A. Bitew (ORCID: https://orcid.org/0000-0003-3684-9316)
- Lamba Omar Sangaré (ORCID: https://orcid.org/0000-0003-3564-7798)
- Yoshiki Yamaryo‐Botté (ORCID: https://orcid.org/0000-0002-9349-4411)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- University of California, Davis (US)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-17
- DOI
- https://doi.org/10.1038/s41467-025-66137-5
- Citations
- 1
- Primary Topic
- Toxoplasma gondii Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.05
Funders
- Université Grenoble Alpes
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Indo-French Centre for the Promotion of Advanced Research
- Fondation pour la Recherche Médicale
- Centre National de la Recherche Scientifique
- National Institutes of Health
- University of California, Davis